Drexel University

NIH Research Projects · FY 2025 · 2025-09

Sickle cell disease affects 100,000 Americans and millions world-wide: a mutation in the β-globin gene gives rise to a hemoglobin variant (sickle hemoglobin, or HbS) that is prone to self-assembly. The resulting protein fibers distort red blood cells and cause the disease’s pathology. Two gene therapies have recently been approved for treatment of this disorder; both are based on the observation that co-expression of fetal hemoglobin (HbF) reduces the formation of sickle fibers. However, we lack a mechanistic understanding of how HbF achieves its anti-sickling effects; simple models in which HbF is suggested to reduce fiber nucleation by diluting HbS fail to explain HbF’s observed actions. Hence, advances in gene delivery have outpaced our basic knowledge of how a given gene product is functioning. This gap in understanding limits both the informed optimization of these new gene therapies, as well as rational approaches to designing potential novel combination treatments. In an alternate approach, high-throughput screening has been used to identify large numbers of potential anti-sickling compounds, drawn from pools of FDA-approved drugs or agents already assessed in clinical trials. However, this promise dims in light of our ignorance of how well their success in the screening translates into actual anti-sickling effects. Again, this knowledge gap will limit efforts at rational optimization. We have identified three critical aspects of HbS pathophysiology for which our lack of understanding poses a significant barrier to rational development and optimization of therapeutic approaches. Aim 1. Developing a mechanistic understanding of how HbF modulates HbS polymerization. The issue: HbF copolymerization with HbS is not understood and poorly characterized. Our hypothesis: Sickle fibers can accommodate vacancies within the polymer that allow HbF inclusion. Our approach: We will measure copolymerization to test our model for HbF incorporation into fibers. Aim 2. Reconciling in vitro and in-cell polymerization. The issue: Fiber formation rates in cells expressing both HbF and HbS disagree with predictions from solution. Our hypothesis: Hb concentration in HbF-containing cells is lower than expected, slowing fiber formation. Our approach: We will measure intracellular concentration and fiber-formation rates simultaneously in live cells. Aim 3. Probing the mechanism of action for newly identified anti-sickling compounds. The issue: Initial high-throughput screens failed to rule out hits that succeed by diminishing oxygen delivery. Our hypothesis: Some compounds flagged as hits in a cell-based assay actually alter O2 affinity, and as such will perform poorly in vivo. Our approach: We will measure binding curves, solubility, and assembly kinetics under low pO2. This work will, in effect, provide the missing “owner’s manual” for the gene and drug therapies that offer so much promise to those suffering from sickle cell disease.

NSF Awards · FY 2025 · 2025-09

A central goal in neuroscience is to understand how networks of neurons process information to generate behavior. Recent advances in imaging have produced detailed maps of brain networks, including individual connections (synapses) between neurons. Yet it remains unclear how to best use these maps to build accurate models of how the brain works. This project will investigate whether neurons integrate information in a surprisingly simple way: by treating all incoming signals equally, regardless of where they land on the neuron's branching input structure, called dendrites. If this “dendritic democracy” proves to be a common feature, it would allow researchers to streamline complex brain models while preserving their accuracy, vastly enhancing computational speed and paving the way for energy efficient, brain inspired AI biotechnologies. The project will also include a strong educational component, integrating findings into high school neuroengineering modules and providing summer research fellowships for students. High school students will use low-cost tools and real behavioral data to explore how brain circuits drive behavior, gaining early exposure to neuroscience, computation, and machine learning. In addition to its scientific contributions, the work will result in publicly available simulation tools, machine learning pipelines, and curriculum materials that support computational neuroscience and STEM education. This project will evaluate the extent to which dendritic democracy, defined as the passive equalization of synaptic input effectiveness across dendritic locations, is a generalizable feature of Drosophila melanogaster neurons and how it influences the interpretation of electron microscopy (EM)-derived connectome data. The investigators will use detailed multicompartment neuron models, constrained by EM morphology and experimentally measured passive properties, in combination with in vivo electrophysiological validation. A central question is whether synapse number alone is sufficient to predict postsynaptic responses during realistic spatiotemporal activation, or whether accurate modeling requires incorporating dendritic structure and synapse location. The project aims to clarify when simplified neuron models provide sufficient explanatory power and when more complex representations are required. To address this, the investigators will apply machine learning approaches to explore the parameter space supporting dendritic democracy and will develop complementary analytical tools rooted in biophysical theory. These tools will be used to evaluate neurons from multiple brain regions, producing general principles to guide modeling strategies for EM datasets in both Drosophila and other species. This project is co-funded by the Directorate for Biological Sciences Activation Program in the Neural Systems Cluster of the Division of Integrative Organismal Systems and by the Division of Emerging Frontiers. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

Project Summary As the body’s systemic circulatory pump, the heart undergoes billions of contraction-relaxation cycles in the lifespan of an individual. This steadfast systolic and diastolic function is owed to cardiomyocytes (CMs) and in-between (“interstitial”) cells such as cardiac fibroblasts (cFBs) and the extracellular matrix (ECM) they produce. Cardiovascular (CV) diseases are the most common causes of mortality worldwide, and congestive heart failure (HF) makes up a a significant proportion of CV deaths. HF is associated with cFB activation, fibrosis, and ECM stiffening, and carries a substantial burden of morbidity, hospitalization, and mortality. Therefore, establishing new therapies for prevention and reversal of HF (among other diseases) will require greater knowledge of cFB function and homeostasis. Using unique mouse models of cardiac loading and unloading, I have found that levels of transcription factors Klf2 and Klf4 within resting (“quiescent”) cFBs are responsive to pressure and volume changes in the myocardium. I have also found that fibroblast-specific deletion of Klf2/4 in mice causes enlargement and thinning of the cardiac ventricle, a process known as eccentric remodeling that is commonly observed in HF. Loss of Klf2/4 in cFBs also results in histological changes to collagens and ECM proteoglycan, leading to progressive injury and fibrosis over time. A better understanding of Klf2/4 mechano-responsive function in cFBs, including roles for their effector genes, will shape clinical and translational pursuits in diseases like HF. The proposed research will advance my skills in modeling adult cardiovascular physiology and pathology – both in vitro and in vivo. As my prior postdoctoral research was in developmental biology, I will use the award period to pivot my career toward adult cardiac homeostasis and pathology, and to grow into an independent scientist within the training environment of my primary mentor, Dr. Mark Kahn, and the University of Pennsylvania Cardiovascular Institute (Penn CVI). I will also gain immense knowledge and wisdom from my advisory committee, which is made up of esteemed researchers (including CVI cardiologist-scientists) with expertise in heart failure, metabolism, collagens, and cFBs. Besides gaining experience in adult cardiac physiology and disease, which is new for me, I will undertake a career development plan with active mentorship, international presentation and networking, as well as leadership and lab management training. The proposed studies will establish new models of cFB mechanical signaling, and will probe Klf2/4 function in the heart in health and disease. By understanding how Klf2/4 affects cFB signaling, activation, and synthesis, this work will uncover potential pathways and molecules of therapeutic value. Moreover, I anticipate generating new tools and unbiased datasets during the award period that will become the underpinnings of my early career as an independent investigator.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Title: A longitudinal cohort study of Plasmodium vivax relapses in Central Africa Plasmodium vivax (Pv) infections caused by relapse are an important cause of morbidity and source of transmission in malaria endemic areas. Relapses contribute significantly to the challenges in controlling and eliminating vivax malaria. Historically, vivax malaria was considered rare or absent in Central and West Africa because of the dominance of Duffy-negative individuals, who lack expression of the Duffy Antigen Receptor for Chemokines (DARC) Pv required for erythrocyte invasion. However, there is growing evidence documenting Pv cases across different parts of Central and West Africa, beyond its endemic range in the Horn of Africa. Prior studies provide compelling evidence that Duffy negativity is not a definitive barrier to Pv invasion and the potential of widespread Pv transmission within Africa. Relapses are known to account for a high proportion of recurrent Pv infections across diverse geographic locations. In Africa, Pv is understudied and at the public health front-end, Pv infections are vastly overlooked in large parts of Africa. Despite numerous reports of Pv cases in Duffy negatives from West and Central Africa, most malaria cases in health facilities are considered as Pf and treated with artemisinin-based combination therapy (ACT). Information on the frequency and transmission potential of Pv relapses in Duffy negative Africans are largely unknown. This R21 application will address 1) what proportion of Pv infections has relapses, 2) how often (i.e. periodicity) relapses occur, 3) are relapse parasites genetically more diverse than those in primary infections, and 4) does relapse infection lead to transmission. Because relapsing infections are important drivers of transmission of Pv malaria, the proportion of recurrences caused by relapse and gametocyte carriage of relapse infections are critical to existing malaria diagnosis and antimalarial treatment regimens in Central/West Africa. Our prior study in Buea of Cameroon showed ~10% of febrile malaria cases and ~15% of asymptomatic community samples being Pv and all were from Duffy-negative individuals. This study will employ a longitudinal design to follow up a cohort of Pv-infected individuals with ACT and without antimalarial treatment to systematically examine relapse biology of Pv in Duffy-negative individuals in Cameroon, an understudied region.

NIH Research Projects · FY 2025 · 2025-08

Abstract/ Project Summary Astrocytes are a major class of glial cells in the central nervous system (CNS) and have roles in neurotransmitter homeostasis, ion balance, and maintenance of the blood-brain barrier. How the brain achieves the correct number of astrocytes remains poorly understood. The establishment of proper cell numbers is vital for a healthy CNS. Cellular elimination is a mechanism various tissues employ to sculpt developing structures throughout the body. In the developing CNS, neuronal and oligodendrocyte progenitor cells undergo elimination, modulating the progenitor pool size. Later, following terminal differentiation, immature cells are eliminated to refine circuits. Despite the large body of literature describing elimination in neuronal and oligodendrocyte populations, little is known about whether astrocytes are established similarly. Evidence suggests that immature astrocytes are eliminated in the first postnatal week. Preliminary data indicates that during late postnatal development, astrocyte cell number declines. This suggests that astrocytes are eliminated to sculpt the final population, but the mechanism by which this occurs is not well understood. The goal of this proposal is to investigate cortical astrocytes undergo stage-specific elimination during the first month of postnatal development and determine the mechanism through which this occurs. Aim 1 seeks to determine the precise timing of astrocyte elimination during early postnatal development and the underlying mechanism. This will be accomplished through lineage tracing and cellular-specific ablation to determine whether microglial engulfment facilitates the elimination of astrocyte progenitor cells. Aim 2 will investigate astrocyte elimination during late postnatal development, how this sculpts the mature astrocyte population in the cortex, and whether neuronal activity influences astrocyte survival. The proposed experiments will be performed at Drexel University under the guidance of the sponsor and thesis committee. This project incorporates a training plan with specific training in experimental design, data analysis, scientific communication, and writing. In addition, the training plan incorporates career and professional development through participation in local and international meetings. The overarching goal of this pre-doctoral fellowship is to provide the training and experience needed to pursue a career as an independent researcher in developmental neurobiology.

NIH Research Projects · FY 2025 · 2025-08

Exposure to ambient heat and fine particulate matter (PM2.5) poses many health risks in children, with differences in risk due to differences in both environmental exposure and in susceptibility-related factors. For children, school characteristics may impact both exposure and susceptibility to environmental hazards, given that children ages 5-17 spend about 20% of their time in school. Additionally, differences in educational quality are documented, underscoring the health implications of incorporating the school context in epidemiologic studies of children. Yet, little is known about the extent to which the spatial distribution of school characteristics childhood morbidity. And, little is known about the extent to which the school context can play a role in shaping childhood susceptibility to outdoor environmental exposures. The proposed research seeks to explore relationships between school context, ambient environmental exposures, neighborhood sociodemographic context, and pediatric morbidity in New York State (NYS). The specific aims are to: (1) investigate spatial variations in school context indicators across NYS, analyzing co-occurrences with area-level social and demographic factors, and (2) Evaluate indicators of school physical, educational, and social context as modifiers of the association between ambient exposures (PM2.5 & temperature) and pediatric morbidity, while accounting for correlated neighborhood characteristics. A comprehensive dataset of pediatric emergency department visits and hospitalizations will be linked with fine-scale daily temperature and PM2.5 estimates, and school context data from multiple publicly available sources. Multiple analytic methods will be used, including machine learning for dimension reduction and spatial methods (Aim 1), and distributed lag nonlinear models in both a frequentist and spatial Bayesian framework (Aim 2). With >12 million health records across 15 years (2005-2019), analyses will be well-powered to evaluate these complex relationships. Findings can be used to inform investment in schools to protect pediatric health, aligning with the NIEHS’s priority research areas. The training plan, developed by Lisa Frueh, MPH (PI) and Jane E. Clougherty, MsC, ScD (sponsor), supports the research activities and training goals. Frueh (PI) will leverage research, training, and professional development resources at the Drexel University Dornsife School of Public Health, a leading public health university in the US which fosters interdisciplinary collaborative research. Together, the proposed research and training plan, supported by institutional resources and the mentorship team of Dr. Clougherty and interdisciplinary collaborators, will support the PI’s career goals.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Despite health protections of the Safe Drinking Water Act (SDWA), contaminants of concern continue to emerge in public water systems (PWS). ‘Unregulated’ contaminants are addressed in the SDWA by the Unregulated Contaminant Monitoring Rule (UCMR), which mandates sampling of PWS for a newly developed list of unregulated contaminants of concern, every five years. The UCMR program, currently in its fifth cycle, has identified contaminants in a systematic way across PWS that serve the majority of the U.S. population. Several chemicals which were frequently detected in the UCMR are suspected or known carcinogens, such as industrial chemicals 1,4-dioxane and per- and polyfluoroalkyl substances (PFAS) and metals including cobalt and chromium-6. Disinfection byproducts also continue to be a major category of concern, even as water treatment approaches change; for example, chlorate (a byproduct of chlorine dioxide disinfectant) was detected in 69% of PWS in 2014-2016. The objective of this proposed study is to examine cause-specific cancer mortality in relation to levels of unregulated contaminants in PWS. We will conduct our investigation through linkage of individual survey records from one of the largest defined cohorts in the U.S. – the Mortality Disparities in American Communities (MDAC) cohort from the U.S. Census Bureau – with measurement of unregulated contaminants in PWS from UCMR sampling. Among U.S. adults in the MDAC cohort, over a study period from 2008-2019, we will estimate associations between unregulated contaminants in PWS and cause- specific cancer mortality. Drinking water contaminants will be examined both individually and as mixtures for their associations with cancer mortality risks. Our study will be the first of its kind to leverage mandated PWS monitoring results through linkage with individual-level cohort data in an examination of cancer risks from unregulated drinking water contaminants. Given the geographic representation of our study to the U.S. population, the size of the study population (>3 million adults), and the resolution of exposures to PWS service areas, this project will provide a realistic overview of the contribution of particular unregulated contaminants on cancer mortality and a high potential for translation to policy.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The study of how prior knowledge shapes new experiences is central to the science of memory and its role in pathology, but there is a critical lack of understanding of how prior knowledge shapes the long-term storage and transformation of a new memory. Current explanations of how episodic memories change over time put forward the hypothesis that neural traces in the hippocampus become distributed across cortical regions (systems-level consolidation), a process that unfolds over extended timescales through persisting neural dynamics that unfold after learning. Emerging evidence conflicts with this, suggesting that prior knowledge can speed or even bypass this process, such that increased cortical dynamics during and after learning results in the immediate generation of a cortical memory representation that supports a stabilized memory (rapid consolidation). However, current research focuses mainly on the impact of prior knowledge on memory accessibility, rather than characterizing the quality of the enduring memory and its assimilation with other information, leaving open questions about how prior knowledge governs the transformation of new memories and their integration into pre-existing cortical networks. This application describes a 5-year plan to investigate how prior knowledge can enhance or distort new memories, focusing on ways that prior knowledge shapes learning and consolidation of new events. The plan consists of functional neuroimaging (fMRI) and non-invasive brain stimulation techniques (TMS), applied to both well-validated and novel experimental approaches and targeting healthy human adults. The central hypothesis is that, if prior knowledge is activated during new learning, memory for new items undergoes rapid consolidation, regardless of if the encoded event is congruent with or conflicts with the activated knowledge. Specifically, the activation prior knowledge during learning will increase cortical involvement during learning and elevate cortical based neural dynamics in periods of awake rest after learning, relative to more hippocampal based processing predicted by classic systems consolidation models. Critically, the rapidly consolidated memories would be both more durable and more easily integrated with prior knowledge than if they were unrelated to prior knowledge. Aim 1 will test these hypotheses with the prediction that new memories that are congruent with prior knowledge will become more integrated with each other, using a novel test of behavioral integration. Aim 2 will test parallel hypotheses when new experiences conflict with prior knowledge, using a well- validated experimental design. Critically, the prediction is that the same rapid consolidation processes would give rise faster and greater distortions in these memories. Completion of these aims will reveal novel insights into how prior knowledge impacts the trajectory of new memories and will shed light on how dysfunction in this process leads to pathology. This has the potential to aid clinical researchers in the development of treatments for patients suffering from subtle impairments in memory, such as stroke patients.

NIH Research Projects · FY 2026 · 2025-08

PROJECT ABSTRACT The proposed longitudinal cohort study aims to understand the development of loneliness and social isolation among autistic young adults, focusing on the impact of social disruptions such as life transitions during young adulthood. Despite the growing concerns over loneliness affecting 27%-40% of young adults globally, very little is known about how changes such as shifts in service systems, employment status, educational transitions, and residential mobility impact the social connectedness and wellbeing of autistic young adults. Examining the projective and risk factors contributing to or mitigating the impact of social disruptions on loneliness is a critical starting point for developing effective intervention and implementation strategies. Young adulthood is a pivotal yet challenging phase for autistic individuals, marked by frequent social disruptions and diminished opportunities for meaningful social interactions. Unlike their neurotypical peers, autistic young adults face the layered challenges of navigating crucial life choices, such as employment, education, and social relationships, against a backdrop of losing familiar social structures and support systems previously provided by education settings. Moreover, this life stage often involves increased encounters with predominantly neurotypical groups, where experiences of nonacceptance and misunderstanding can exacerbate feelings of disconnection, presenting unique social challenges. Our study will enroll 375 autistic young adults aged 18-30 who are approaching significant life transitions (e.g., starting a new job, entering college, or losing services). Over the course of two years, we will characterize the trajectories of loneliness and social isolation associated with these social disruptions, using latent growth mixture modeling to identify distinct subgroups and assess demographic variations. Then we will evaluate the association between changes in loneliness and social isolation and a range of adult outcomes, including social, health, and psychological dimensions. Using a mixed-method approach, we will delve into protective and risk factors—structural, interpersonal, and social—that influence the impact of social disruptions on loneliness, using both quantitative data and in-depth qualitative interviews to gain a comprehensive understanding of these dynamics. Guided by the meaningful interaction framework and insights from autistic community partners, the completion of this study will result in the most substantial work to date to identify modifiable interpersonal, system, and policy factors to mitigate the impact of social disruptions. This will inform targeted interventions and improve service delivery, enhancing the quality of life and wellbeing of young autistic adults and addressing a pressing public health need.

NSF Awards · FY 2025 · 2025-08

Mechanical metamaterials, i.e., engineering materials whose properties arise from geometry rather than chemical composition, hold great promise for applications in aerospace, biomedical engineering, robotics, and beyond. By integrating active elements, these materials can respond dynamically to environmental stimuli such as heat or light, enabling adaptive and programmable behavior. Despite their potential, the practical design of such materials remains constrained by computationally expensive and highly specialized modeling tools. This award supports fundamental research that seeks to establish a general, experimentally validated continuum modeling framework for active mechanical metamaterials. This framework looks to enable efficient prediction of material behavior and systematic design across a wide range of geometries and actuation mechanisms. The project seeks to advances fundamental understanding while supporting technological innovation in advanced manufacturing, adaptive devices, and reconfigurable structures. It also leverages interdisciplinary collaboration and integrated fabrication-modeling workflows to train students across educational levels and to engage the public through outreach initiatives. The research integrates theoretical, experimental, and computational approaches. A continuum modeling framework will be constructed to connect unit-cell geometry with macroscopic deformation, including both planar and three-dimensional behaviors. The models will incorporate internal variables and compatibility conditions to capture soft deformation modes and the effects of actuation. Experimental work looks to validate the framework through fabrication, including direct ink writing, molding, and conventional 3D printing, and mechanical testing of passive and active metamaterials, making use of digital image correlation to quantify deformation. A systematic scaling study intends to define the limits of continuum applicability. The final phase will implement the models into finite element simulations to enable inverse design, seeking to allow metamaterials to be tailored for specific responses. Collectively, these efforts seek to yield general design principles and computational tools to accelerate the adoption of mechanical metamaterials in advanced engineering applications. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract In vertebrate neurons, axons have a nearly uniform microtubule polarity pattern with mostly plus-end-out microtubules, while dendrites have a mixed microtubule polarity pattern with about half of the microtubules having each orientation. These distinct microtubule polarity patterns are fundamental to the morphological and compositional differences that define these two types of neuronal processes. However, a question that often arises is how organelle transport can function in dendrites if microtubules of both orientations are interspersed. Would organelles not move back and forth futilely as they come off one microtubule and then associate with another of the opposite orientation? Recent studies have shown that in hippocampal neurons, the microtubules of each orientation are spatially segregated, with the minus-end-out microtubules coalesced into centralized bundles and the plus-end-out microtubules dispersed around the bundles. This appears not to be the case for the dendrites of all types of neurons, but only the dendrites of certain types of neurons, presumably those with the need for higher efficiency in organelle transport. What accounts for the segregation of microtubules of opposite orientation in these dendrites? Posited here is that the answer lies with a newly discovered slice variant of MAP4, called oMAP4, which has the same microtubule-binding domain as the classic MAP4, called uMAP4, but an entirely different projection domain. uMAP4 has been shown to regulate which molecular motor proteins can interact with microtubules. Unlike uMAP4, oMAP4 is endowed with strong microtubule crosslinking properties. Preliminary data obtained by the applicant, Julie Schaub, indicate that oMAP4 is strongly expressed in hippocampal neurons, where it is highly enriched on the centralized bundles of microtubules. The overarching hypothesis of this proposal is that uMAP4 regulates transport via the motor proteins that move organelles along plus-end-out microtubules, while oMAP4 bundles the minus-end-out microtubules and thereby segregates them from microtubules of the opposite orientation. To investigate this hypothesis, rat brain tissue as well as primary cultures of rat neurons will be probed with antibodies to uMAP4 and oMAP4, the latter of which were generated and validated by the applicant. In addition, the impact of experimental manipulation of uMAP4 and oMAP4 levels will be assessed, and cutting-edge microscopy techniques will be used to evaluate the hypothesis. The proposed work has medical relevance because little is known about how corruption of the dendrite’s microtubule array contributes to dendritic atrophy in neurodegenerative diseases like Alzheimer’s, where it is already known that MAP4 expression is altered. In addition to conducting the proposed research, the applicant will undergo a rigorous training program in the neurosciences that includes scientific meetings, journal club, lab meetings, one- on-one meetings with her sponsor, twice annual meetings with her dissertation committee, career education, a panoply of seminars/discussions on skills needed for success, and a rich environment of collaborators and colleagues from across the biomedical sciences.

NIH Research Projects · FY 2025 · 2025-07

Project Summary: The immune system plays a pivotal role in tissue healing after traumatic injury and in chronic inflammation associated with autoimmune diseases. Macrophages are professional phagocytes (cell-eating cells) of the innate immune system that ingest apoptotic cells (ACs) for nutrient recycling and cellular turnover to maintain tissue-level homeostasis. Internalization of ACs (known as efferocytosis) has long been known to be a trigger for the phenotypic switch of macrophages into a reparatory state. Furthermore, dysregulation of efferocytosis has been shown to contribute to pathologies such as atherosclerosis, cancer, and rheumatoid arthritis. Interestingly, the processing of apoptotic cellular cargo by macrophages releases metabolites (such as nucleotides, amino acids, polyamines, lactate, and fatty acids) that alter the metabolic status of the phagocytes— promoting fatty acid oxidation (FAO) and pro-reparatory phenotype. Here, we will test the hypothesis that this physiological pro-healing response can be triggered in macrophages via nanoparticle-based delivery of AC- mimetic metabolite payloads. We have developed a simplified AC-mimetic cargo-delivery system based on cyclodextrin nanoparticle (CDNP), which is known to be rapidly and preferentially uptaken by macrophages. Here, we will (a) sequester fatty acid payloads within CDNPs (providing “the fuel” for FAO), (b) encode immunomodulatory diamines (such as putrescine and spermidine) directly within the CDNP core, (c) test the uptake of loaded CDNPs by macrophages in vitro, and (d) examine the temporal changes in the transcriptome and functional phenotype of macrophages that result from CDNP uptake. Using primary murine and human macrophages in vitro, we will test if cell-targeted delivery can produce transcriptomic and translational signatures indicative of reparative phenotype. Macrophages will be monitored via morphometric (fluorescence microscopy), transcriptomic (nanoString), and proteomic (Luminex) tools for phenotyping. Results will demonstrate the propensity for stimuli (diamines as “the spark”) and a metabolic driver (fatty acids as “the fuel”) to act either individually or synergistically to promote a reparative state. We will determine the uptake mechanism of CDNPs loaded with lipid cargo—identifying critical cell-surface receptors, endosomal escape routes of metabolites into the cytosol, and the intracellular signaling mechanisms. Metabolic changes, such as increase in FAO, will be studied using Seahorse assay and mass spectrometry. Finally, we will test whether the metabolism-targeted strategy of macrophage phenotypic modulation can synergize with pharmacologic strategies (e.g., delivery of anti-inflammatory drugs) for developing an effective therapeutic modality to prevent chronic inflammation. Completion of these aims would validate the feasibility of metabolic reprogramming of macrophage phenotype via nanoparticle-mediated intracellular delivery of AC-mimetic metabolites. Although our proposed project is limited in scope to in vitro studies, its success will enable the healing potential of the innate immune system to be harnessed for regenerative medicine, including in the context of traumatic injury or autoimmunity.

NIH Research Projects · FY 2025 · 2025-07

One of the primary impediments to curing HIV is the existence of viral reservoirs in distinct compartments and cell types that are unaffected by current antiretroviral therapies (ART). In the central nervous system (CNS), reservoirs are comprised primarily of myeloid cells, such as microglia and perivascular macrophages. Because HIV enters the CNS rapidly after initial infection, these reservoirs are established prior to initiation of ART. While ART can enter the CNS and block the infection of new myeloid cells, it does not stop viral replication from an integrated provirus. Thus, most of our current antiretrovirals have no effect on viral replication from chronically infected myeloid cells allowing long-lived, infected CNS microglia to drive ongoing neuroinflammation and provide a source of HIV for viral recrudescence. To prevent this, it is critical to precisely target viral replication in these cells. Existing strategies to eliminate this reservoir have shown some promise in pre-clinical studies but have not yet proven successful. This proposal pursues a novel, alternative strategy: employing RNA interference (RNAi) to durably silence HIV transcription in myeloid cells. This will stop viral replication from these cells and functionally eliminate the CNS reservoir through the “block and lock” strategy. To do this, we will evaluate an approach that uses small RNA to induce transcriptional gene silencing (TGS) of the integrated LTR. Our preliminary studies demonstrate the efficacy of inducing TGS through RNAi and also show changes in viral output in chronically infected myeloid populations treated with ART. The state of viral output in myeloid cells is distinct from T-cell latency and is increased by exposure to benzodiazepines. We hypothesize that treatment with RNAi will induce a stable heterochromatic state, blocking proviral transcription and eliminating production of new virions in chronically infected microglia. Thus, we have proposed studies that will develop our RNAi based strategy to eliminated virion production in infected myeloid populations, providing an effective strategy by which to nullify the CNS myeloid reservoir. Successful completion of this screen will provide necessary data for further applications exploring specific applications of this technology and examination of transcriptional dynamics in microglia using the described systems. To carry out these studies, we propose the following Aim I: To identify and optimize LTR targeting RNAi for transcriptional silencing of HIV in myeloid cells and Aim II: To determine the efficacy of RNAi candidates in iPSC-derived human microglia and durability after LRA and benzodiazepine treatment.

NSF Awards · FY 2025 · 2025-07

Combinatorics is an area of mathematics concerned with analyzing, organizing, and optimizing over discrete data. It is a fundamental tool in many scientific areas such as genomics, computer science, statistics, and physics. This project will develop combinatorial methods for attacking problems in Lie theory and symmetric function theory, areas with applications to probability, statistical mechanics, and quantum information theory. A mutually beneficial component is the further development of the SAGE open-source mathematics software, a crucial tool for this investigation. Also graduate students will be trained as part of this project, This project addresses combinatorial problems tied to representation theory, algebraic geometry, and physics, with a focus on Macdonald polynomials and Schubert calculus. Macdonald polynomials are a remarkable family of orthogonal polynomials which form a basis for the ring of symmetric functions. Since their introduction in the 80's, they have developed connections with many areas, including Hilbert schemes, the Calogero-Sutherland model in particle physics, and knot invariants. In the 90's, Garsia and Haiman studied transformed versions of Macdonald polynomials, which they connected to the representation theory of polynomial rings, generalizing classical results of Chevalley, Shephard-Todd, and Steinberg on reflection groups. A separate line of work initiated by Cherednik, Macdonald, and Opdam in the 90's investigated nonsymmetric versions of Macdonald polynomials, which clarified the theory and connected it to affine Hecke algebras. The PIs and collaborators recently discovered a way of transforming these nonsymmetric versions in the same style as Garsia and Haiman did for the symmetric case. Further study of these new polynomials will unearth new representation theoretic and combinatorial mysteries of nonsymmetric Macdonald polynomials. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-07

NON-TECHNICAL SUMMARY Dislocation, a type of crystalline defect caused by the linear misalignment of atoms, plays a crucial role in determining the mechanical properties of metallic materials during processing and service. This Faculty Early Career Development (CAREER) award supports a research and education project aimed at understanding how dislocations move and how their motion affects the deformation behavior of a class of materials known as concentrated solid-solution alloys (CSAs). In CSAs, different atomic species are randomly mixed in high concentrations, creating locally varied chemical compositions throughout the crystal lattice and spatially fluctuated energy barriers to dislocation motion. These unique atomic-scale features cause dislocations in CSAs to behave differently from those in traditional alloys, leading to mechanical characteristics that are not yet fully understood. This research project integrates statistical theories, computational modeling, and experimental validation to develop a framework for quantitative predictions of dislocation motion in CSAs. By focusing on CSAs made from multiple refractory metals like niobium, molybdenum and tungsten, the project aims to reveal how local chemical fluctuations influence dislocation motion and how these mechanisms shape the strength and plasticity of CSAs. The knowledge being generated could lead to new design strategies for novel refractory alloys with superior mechanical properties and room-temperature processability, addressing critical material needs in industries essential to energy and national security, including nuclear energy, electric power generation, and hypersonic aviation and aerospace. This project also emphasizes education and outreach to engage students of all ages in materials science and engineering (MSE). It offers hands-on, specifically tailored research training for college students of different grades, introduces high school students to engaging topics in materials science, and incorporates artificial intelligence knowledge into the MSE classroom, with the overarching goal of preparing the next generation of scientists and engineers with the necessary knowledge and skills for developing stronger, more durable materials for future technologies. TECHNICAL SUMMARY This CAREER award supports an integrated research and education project to understand dislocation glide behavior and its effect on plastic deformation in concentrated solid-solution alloys (CSAs). In these alloys, non-dilute atomic mixing introduces inherent fluctuations in local lattice chemistry, making the energy barriers to dislocation glide (i.e., Peierls barrier) vary randomly from one lattice location to another. Consequently, dislocations in CSAs behave distinctively from those in traditional dilute alloys, resulting in intriguing strength and plastic properties that remain poorly understood. By integrating statistical theories, multiscale dislocation modeling, and experimental validation, this project is developing a probabilistic framework for describing Peierls barrier variations and dislocation glide dynamics in CSAs. Using body-centered cubic (bcc) CSAs of refractory metal elements as a model system, five objectives are pursued: (1) establishing a statistical representation of local chemical fluctuations; (2) predicting probability distribution functions (PDFs) of unstable stacking fault (USF) energies based on the statistical representation; (3) developing probabilistic descriptions of Peierls barriers for different slip systems based on the PDFs of USF energies; (4) elucidating dislocation glide mechanisms using the probabilistic Peierls barriers; and (5) explaining and predicting deformation behavior of bcc CSAs with experimental validation, focusing on brittle-to-ductile transition and activation of slip multiplicity. The knowledge being generated in this project could open new pathways for improving the room-temperature toughness and ductility of bcc CSAs, thereby advancing their applications in industries vital to energy and national security, including nuclear energy, power generation, aviation and aerospace. The statistical approaches being developed are also transferable to the study of probabilistic behavior for crystalline defects in other chemically complex material systems. This project also includes a significant educational component that ignites passion and cultivates interest in material science and engineering (MSE) among students of various ages. Building on the scientific findings from the research component, the educational component offers multidisciplinary learning and training opportunities for undergraduate students across all levels, sparks early interest in MSE among high school students, and advances the integration of materials informatics into the MSE curriculum. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-07

Project Abstract: The mortality rate from influenza viral (IV) infection is highest in infants less than age six months, currently an age group not eligible for the available influenza vaccine, but the mechanisms for this clinical observation are not well understood. Vulnerability to respiratory viruses during infancy is likely manifested by both immature lung and immune systems. To understand these age-specific differences of immune and pulmonary function at the air-blood interface in the developing lung, an age-appropriate pre-clinical neonatal murine IV infection model is employed. Previously, we demonstrated that murine neonates are exceptionally susceptible to IV infection, with an early loss of viral control indicating an aberrant neonatal pulmonary innate immune response. Both Type I interferons (IFN-I, IFNα and IFNβ) and type III interferons (IFN-III, IFNλ) are critical components of this innate immune response. In adults, IFNs promote antiviral states following IV infection, but can also prolong lung repair. In infants, there is a gap in knowledge about the age-specific role of IFN-I and IFN-III in IV response. To address this knowledge gap, experiments with IFN receptor transgenic mice demonstrate 5 key findings. First, neonatal mice with a defective IFN-I receptor (Ifnar1-/-) infected with PR-8 IV had an improved survival rate of 80%, compared to the WT survival rate of 15%, despite having similar viral loads. In direct contrast, murine neonates with deletion of the IFN-III receptor (Ifnlr1-/-), similarly infected with IV, all succumbed to infection. Moreover, in vivo IFNβ treatment after IV infection accelerated death in murine neonates. To determine potential mechanisms of IFN-I toxicity, we demonstrated that IFNβ directly led to increased ROS production in neonatal alveolar epithelial and immune cells, but not in the adult. Finally, depletion of neutrophils, one of the primary producers of ROS, protected murine neonates. Therefore, the neonatal propensity to produce ROS in response to respiratory virus, coupled with a global antioxidant deficiency in the neonate, creates an oxidative stress imbalance. Our overarching hypothesis is that in the IV-infected developing lung, IFN-III modulates neutrophils to control pro-inflammatory cytokine and ROS production. Through a previously established collaboration, the goal of this exploratory project is to identify the molecular pathways of developmental differences in the neonatal neutrophil response to IFN-I and IFN-III. Furthermore, we will determine the impact of IFNλ on neutrophil reactive oxygen and nitrogen species production, in vitro and in vivo. Using a unique neonatal murine pre-clinical model of IV infection, coupled with an established bioinformatics pipeline, we will identify key molecular pathways in the neonatal neutrophil response to respiratory viruses and how IFN-III can potentially modulate these pathways, by impacting ROS/RNS production and tempering the pathogenic neutrophil response in neonatal IV infection. Our studies will bring forth new understanding of infant mucosal immunity to develop targeted therapeutics for the infant population.

NIH Research Projects · FY 2025 · 2025-06

Research Abstract Single neurons perform complex computations that depend critically on the interactions between often precisely targeted synaptic inputs and the intrinsic active and passive properties of the neuron. While some functional implications of synaptic topography and intrinsic properties for neural computation have been explored, their interactions remain poorly understood. Difficulties in simultaneously localizing synaptic inputs, effectively activating synapses with realistic time courses and functional tuning, and manipulating neuron intrinsic properties, pose challenges in exploring these interactions which collectively shape neuronal computations. This study aims to address this gap by using a combination of computational and experimental approaches, focusing on the looming detection circuits of the fruit fly Drosophila melanogaster, which drive motor responses to objects approaching on a direct collision course. These circuits contain descending neurons (DNs) that integrate overlapping inputs from visual projection neuron (VPN) populations, that encode different features of the looming stimulus (such as angular velocity or size). By leveraging experimental access to VPNs and DNs, together with the comprehensive electron microscopy dataset of the full adult fly brain, we develop detailed biophysical models to investigate how the spatiotemporally realistic activation of VPN synapses influences integration processes and interacts with intrinsic properties of DNs. Through experimental manipulations and computational simulations, we aim to uncover the mechanisms that underlie the integration of synaptic inputs in DNs to drive realistic responses. Overall, this study will provide insights into visual feature integration within VPN-DN circuits and general mechanisms underlying dendritic integration.

NSF Awards · FY 2025 · 2025-06

This I-Corps project is based on the development of self-healing fibers for concrete applications. Concrete is the most widely used construction material in the world, forming the backbone of critical infrastructure such as buildings, power plants, bridges, highways, and dams. However, cracking in concrete remains a persistent and costly issue, leading to shortened service life, frequent repairs, and significant disruptions. In the U.S. alone, billions of dollars are spent annually on maintaining and repairing aging concrete infrastructure. These repairs not only incur direct financial costs but also cause indirect losses through downtime, traffic delays, and reduced community resilience. This technology provides a solution by embedding self-healing fibers into concrete, enabling self-repair of cracks in concrete without external intervention. In addition, this innovation has the potential to reduce maintenance needs, extend infrastructure lifespan, and minimize service interruptions. The commercial impact spans construction, transportation, energy, and defense sectors where durable and low-maintenance concrete infrastructure is critical. This technology also may enhance the resilience of communities by ensuring safer, longer-lasting structures and reducing the economic and logistical burdens associated with frequent repair and reconstruction. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of adding multifunctional, polymer-based, self-healing fibers to concrete. The fibers are made multifunctional using a three-in-one solution design to enhance fracture resistance, enable damage-responsive activation, and deliver autonomous self-healing in concrete. This solution is accomplished by functionalizing polymeric fibers with a micron-thick alginate-based hydrogel layer containing healing agents, including bacterial spores. The hydrogel layer is encapsulated within an outer protective shell that is tunable and strain responsive. The protective shell prevents premature activation during normal concrete service conditions and ensures targeted healing activation only when a crack occurs. The functionalized fiber is designed to enable selective and efficient self-repair and also enhances mechanical performance of concrete systems through fiber reinforcement. Unlike other self-healing systems, such as microcapsule-based technologies that lack structural reinforcement and activate indiscriminately, this technology maintains the load-bearing capabilities of commercial polymer fibers while adding tunable healing functionality. The underlying research includes advanced manufacturing, materials synthesis, coating stability, and mechanical testing in cementitious composites that demonstrate the mechanical performance and controlled healing behavior of the fiber. This technology may extend the lifespan of concrete infrastructure and improve the resilience of built environments. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-05

Abstract Organizations such as the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommend that adults eat a diet rich in whole grains, vegetables, and fruit; limit consumption of “fast foods” and other processed foods high in fat, starches, or sugars; and limit consumption of red and processed meat and sugar sweetened beverages (SSBs). The degree of adherence to these dietary guidelines predicts cancer incidence and cancer-related mortality. Primary prevention programs that facilitate sustained adherence to these dietary recommendations are sorely needed. The proposed study will evaluate the efficacy of a preventive intervention informed by the profound influence the food environment has on eating behavior. Our team pilot tested the planned approach and intervention delivery with a factorial design, yielding data on feasibility, acceptability, and effect sizes that informed the optimization of the experimental intervention components. In the proposed study, index participants (n = 236) will be randomized to either receive nutrition education (i.e., control group) or the experimental intervention, which is referred to as “Eatwell.” Both conditions will provide an equal number of group sessions held remotely over a period of 18 months. The curriculum in both conditions will be mindful of social determinants of health. In the Eatwell condition, grocery shopping will be the primary intervention target, with the goal of maximizing availability of healthy foods and limiting availability of unhealthy foods in the home environment. The intervention also will encourage participants to increase the proportion of meals prepared at home to take advantage of the optimal defaults present there, and teach strategies to manage temptation when eating away from home. Eatwell coaches will provide a foundation of nutrition education, teach self-regulation skills, and use innovative methods to enhance motivation for change (e.g., using a digital platform to monitor and provide feedback on grocery purchases). Eatwell will employ a multi-level approach, such that each index participant (i.e., the participant who initiates enrollment) will invite an adult household member to engage in select aspects of the intervention, to increase support for change in the home food environment. We expect that focusing on the home food environment will heighten the intervention impact, improving dietary quality and decreasing cancer risk for all members of the home. Assessments will be completed at months 0, 6, and 18. Dietary intake will be measured with food recalls, yielding a cancer prevention dietary adherence score as the primary outcome. Intake of fruit and vegetables and fiber; ultra-processed foods; red meat and processed meat; and SSBs will be examined as secondary outcomes. The biological impact of the intervention on inflammation will be measured with interleukin-6 and C-reactive protein. Changes in dietary quality among household members will be evaluated. Mediators and moderators of intervention effects will be tested. The findings will be relevant not only to the field of cancer prevention, but to the prevention of other diseases for which dietary quality is important.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY/ABSTRACT System consolidation of memory involves a cortical-hippocampal-cortical loop of information processing; however, it remains unclear how this process is initiated. Converging evidence suggests that slow-wave sleep (SWS) plays an essential role in memory consolidation. During SWS, various cortical regions exhibit a prominent delta oscillation (0.5–6 Hz) that enables coordinated interactions across the brain via synchrony. This delta wave exhibits a cyclic Up and Down pattern: the Up state corresponds to high cortical activity, whereas the Down state coincides with near-total cortical silence. Therefore, each Down state functions as a reset to position key cortical regions for information exchange during the subsequent Up state. One key unanswered question is whether there is a unique group of cortical neurons that primarily drive SWS Down-to-Up transitions for memory consolidation. Utilizing large-scale in vivo recording and advanced analysis techniques, we recently discovered that a distinct subpopulation (~20%) of retrosplenial cortex (RSC) layer-5 neurons initiates firing during SWS Down states. We termed these neurons RSC Down-state assembly (DSA) neurons. Preliminary results revealed that RSC DSA neurons exhibit robust synchrony at SWS Down-to-Up transitions, which precedes the activity of other RSC neurons. Moreover, RSC DSA neurons increased their activity between pre- and post-training sleep after a new learning experience, indicating their role in memory consolidation. The central objective of this proposal is to test our hypothesis that RSC layer-5 DSA neurons play a key role in initiating SWS Up states to drive memory consolidation. Supported by considerable preliminary data, we propose to pursue this objective through the following two specific aims. Aim 1 investigates the neural dynamics of RSC layer-5 neurons in memory consolidation. Aim 2 investigates the connectivity and causal role of RSC DSA neurons in memory consolidation. Results from this study will advance our understanding of RSC neuronal activity dynamics and the delta oscillation generation mechanisms underlying memory consolidation. This could provide insight into the improvement of memory and interventions in memory disorders such as post-traumatic stress disorder.

NSF Awards · FY 2025 · 2025-04

People spend roughly 30-50% of their time thinking about things other than what they are currently doing. Although such “mind-wandering” is often thought of as something to be avoided, recent research suggests that mind-wandering may help to commit memories to long-term storage, a process known as memory consolidation. Mind-wandering and memory consolidation are typically studied separately, but new evidence suggests that these two mental processes use the same neural resources: specifically, the ‘reactivation’ of memories in the brain’s hippocampus region and the activation of a set of connected brain regions known as the default mode network. This project involves development of a new approach based on real-time brain imaging that aims to better understand whether memory consolidation has an impact on the content of spontaneous thoughts—and in turn, whether mind-wandering impacts memory consolidation. The overall goals are to develop a new tool and to advance understanding of how memories are retained for the long term. Additionally, this work includes STEM training and education for undergraduate and graduate students. The project addresses a specific problem that stems from a known feature of reactivation of memory events in the hippocampus: these events support memory consolidation but occur spontaneously at unpredictable times. Given this unpredictability, it is difficult to obtain samples of thoughts or behaviors at the precise time that these reactivation events occur. The goal of this research is to develop a new approach, based on real-time analysis of neuroimaging data, that allows precise alignment in time between memory reactivation events, activation in the default mode network, and samples of thought. In a computational simulation as well as an experiment conducted in human participants, the research uses analyses of multivariate patterns to detect reactivation events in functional Magnetic Resonance Imaging data. The project focuses on verifying that this method can be used in a valid manner within a real-time analysis system to trigger samples of thought that are aligned in time to neural reactivations. Taken together, the research looks to deliver a new tool that can be applied to determine when and how spontaneous thoughts may help or harm the formation of memories, potentially leading to further development of real-time neural measures to trigger interventions for enhancing learning and memory. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-04

This I-Corps project is focused on the commercialization of a unique device that allows people to produce their own plant-based foods and potentially learn about healthy eating, while improving their diet. The technology uses algae to provide fertilizer for vegetable growth and allows for the simple and easy growing of micro-greens, greens, and herbs at home. The countertop device requires little space and no electricity to grow plant-based diet options for people in their homes and kitchens adjacent to where food is prepared. The advancement is designed to help people add affordable, healthy options to their daily routines and to learn about beneficial nutrition. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of a compact, in-home hydroponics device that uses algae to provide fertilizer for vegetable growth. The device uses tap water and has no complex wiring or electronics. The algae grow on the special interior of the device which is configured to create a moist and textured environment that supports the algal needs while still encouraging plant growth. Seedling germination and plant growth in the device takes place over the course of two to three days when growing microgreens and one week when growing other plants. Harvesting is possible within one week for microgreens and two to three weeks for other plants. The algae are hardy and self-regenerating, so they do not require replenishment even after multiple rounds of plant production. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-03

Project Summary Interventions to support clinical and behavioral needs of autistic people are among the most resource- intensive in any field. While it is crucial to advance the use of empirically-supported interventions for this population, it is yet more pressing to understand factors that drive intervention decision-making among practitioners and families regardless of empirical status. With the rise of the neurodiversity movement, which deprioritizes the goals of normalizing behavior or eliminating autism, there has been a rapidly-growing appreciation from stakeholders for interventions consonant with such values, grounded in the experiences of autistic people and other members of the autism community, while still impacting important outcome domains. Thus, the aspiration to implement so-called neurodiversity-affirming interventions (NAI) has become a touchstone in the autism stakeholder community as a marker of value and utility. Indeed, many practitioners are changing the way their practices are advertised to highlight their purported use of NAIs, and families are increasingly considering the NAI label when making decisions about the services they choose for their children. This can directly impact whether families elect to engage in any intervention at all, irrespective of empirical status. However, while NAI is quickly emerging as a new practice domain, no consensus exists about what constitutes a NAI. With scant empirical or theoretical literature, there is no operationalization of the term, and vast space for ambiguity, creating a “carts before horses” problem. Indeed, this has created a crisis for the field, making it impossible to ask empirical questions about whether NAIs impact target outcomes, how they align (or do not) with evidence-based practices, who is doing NAIs, and what features of NAIs cohere as an identifiable practice set. Thus, a tool to measure fidelity of NAI implementation is urgently needed. The goal of this project is to produce such a measure. This project aims to leverage qualitative interviews of relevant experts (autistic individuals and caregivers) to establish a pool of items indicating what they see as the outcomes most affected by NAIs. It will then draw from a national sample to establish a comprehensive, NAI measure that also group-specific variation by of a) autistic individuals, b) caregivers, and c) practitioners, using the initial item set by implementing a multi-round Delphi poll approach to establish consensus. Finally, this study will administer a large national survey of practitioners across clinical and behavioral disciplines that work with autistic individuals, examining internal consistency of the Fidelity measure and its 3 subscales (autistic individuals, caregivers, practitioners), as well as convergent and divergent validity of the measures across practitioner groups, considering demographics, training, outcome targets, and discipline. This work will provide a foundation for future study of NAI, providing a tool to examine the discrete and additive effects of NAI implementation on outcomes in a wide array of evidence-based and community-derived intervention settings.

NIH Research Projects · FY 2026 · 2025-02

Cell movement through three-dimensional (3D) extracellular matrix (ECM) is an essential component of normal physiology and disease, including wound healing and tumor metastasis. Understanding how cells move through structurally diverse 3D matrices will be essential to design therapies aimed at controlling cell migration in the body. During 3D migration, both metastatic tumor cells and wound healing fibroblasts are faced with the same problem: how to efficiently move the bulky, stiff nucleus. While the power of actomyosin contractility is essential for cells to move their nuclei in 3D matrices, it is not understood how it is regulated by the ECM structure or coupled to the influx of water into the cells that is necessary to sustain high-pressure migration. An additional layer of complexity comes from the fact that the 3D matrix structure can govern actomyosin contractility to dictate the type of protrusions cells use to move (i.e. migratory plasticity). By understanding how the structure of the 3D ECM affects actomyosin contractility and water influx, we aim to create a conceptual framework to explain how and why human cells switch between distinct 3D migration mechanisms. We recently discovered that human cells moving in a linearly elastic 3D matrix rely on integrin-based cell-matrix adhesions and the power of actomyosin contractility to pull the nucleus forward, like a piston, and switch from using low-pressure lamellipodia to high-pressure lobopodial protrusions. This project will explore how the cell reprograms its intracellular architecture and polarity to power the nucleus, and thereby the cell through 3D matrices. To achieve these goals, we will focus on three key gaps in knowledge. Question 1: how is the nuclear piston pulling mechanism activated in response to the physical environment? While the nucleus can act as a mechanosensor to control contractility at the rear of the cell, the mechanosensor that regulates the pulling mechanism has not been identified. Question 2: How are organelles and endomembranes organized and transported past the nucleus in compartmentalized, pressurized cells using the piston mechanism? This question will help us understand how the secretion pathways identified addressing question 1 function in high- pressure, compartmentalized cells. Question 3: Once activated, how is the anterior contractility responsible for pulling the nucleus forward sustained over the hours to days that primary human fibroblasts sustain this mode of 3D migration? While contractility at the trailing edge is well known to push the nucleus forward, very little is understood about the longer-term regulation of the pulling forces generated by the piston mechanism. By addressing these questions, our research will establish how distinct pools to actomyosin contractility are linked to the control of cytoplasmic hydraulic pressure to achieve 3D motility. This enhanced understanding of the fundamental principles of directional 3D cell motility and migratory plasticity will lead to new therapeutic strategies to control normal and abnormal cell movement in the body.

NIH Research Projects · FY 2026 · 2025-02

Project Summary Kidney transplants, despite their utility in treating renal failure, carry significant risks, particularly after successful surgery due to the potential for immunological rejection. Aggressive immunosuppressive regimens have been designed to limit this risk but are fraught with side effects such as increased risk of cancer and infection. More precision immunosuppression that selectively generates tolerance towards donor kidney antigens are necessary, but to date no selective therapies have been developed. Here, we present a proof-of-concept study for a cell- based therapy to generate donor-specific immune tolerance. We will engineer potent tolerogenic dendritic cells (tolDCs) that can be infused into donor kidneys prior to transplantation, facilitating presentation of donor antigens and influencing antigen specific T regulatory responses; thereby selectively suppressing only donor specific immunity. Our engineered tolDCs, also known as Push/Pull particle tolDCs (PPP-tolDCs) will contain microparticles loaded with a combination of two synergistic tolerogenic drugs (known as the push/pull particle) that will provide sustained drug release. These push/pull drug combinations were identified via molecular screening and generate tolDCs which influence more potent antigen specific Treg responses. We hypothesize that these two innovations, the push/pull drug combination and encapsulation in sustained release microparticles, will function cooperatively to generate highly potent, long-lived tolDCs, which in turn generate T regulatory responses. In this proposal, we will validate that push/pull drugs can be loaded into microparticles and effectively influence naïve dendritic cells towards tolDCs phenotypes by modulating the inhibitor/agonist loading ratio. We will further explore PPP-tolDCs interaction with donor-specific kidney antigens from various sources and ability to influence donor-specific T regulatory responses. This is the first step in developing PPP- tolDCs towards a cell therapy that can generate donor kidney tolerance by being infused into donor kidneys prior to transplantation.